1-(1-(2,3-dihydro-2-benzofuryl)-alkyl)-4-aminohexahydroisonicotinic acid amides or nitriles

ABSTRACT

1. A 1-(1-(2,3-DIHYDRO-2-BENZOFURYL)-ALKYL)-4-AMINOHEXAHYDROISONICOTINIC ACID AMIDE OR NITRILE CORRESPONDING TO THE FORMULA   (-CH(-R1)-PH-O-)&gt;C(-R2)-CH(-R3)-N&lt;(-ALK(1)-C(-ZO)(-NH-R4)-   ALK(2)-)   WHEREIN PH IS 1,2-PHENYLENE, (LOWER ALKYL)-1,2-PHENYLENE. MONO- OR DI(LOWER ALKOXY)-1,2-PHENYLENE, (LOWER ALKYLENEDIOXY9-1,2-PHENYLENE, (FLUORO OR CHLORO9-1,2-PHENYLENE, (LOWER A-HYDROXYALKYL)-1,2-PHENYLENE OR (LOWER ALKANOYL)-1,2-PHENYLENE, EACH OF R1, R2 AND R3 IS HYDROGEN OR LOWER ALKYL, EACH OF ALK1 AND ALK2 IS LOWER ALKYLENE SEPARATING THE NITROGEN ATOM FROM THE SPIRO-CARBON ATOM BY TOW RING-CARBON ATOMS, R4 IS HYDROGEN, LOWER ALKYL, 3 TO 7 RING-MEMBERED CYCLOALKYL OR H-PH, ZO IS COHNR6 OR CN AND R6 IS HYDROGEN, LOWER ALKYL OR LOWER HYDROXYALKYL, OR AN ALKALI METAL OR ACID ADDITION SALT THEREOF.

United States Patent O US. Cl. 260-29358 6 Claims ABSTRACT OF THE DISCLOSURE 8-[l-(2,3-dihydro-2 benzofuryl)-alkyl] 1,3,8 triazaspiro(4,5)decanes, e.g. those of the formula R=H, aliphatic, araliphatic or aromatic radical or functional derivatives thereof are neuroleptic agents.

CROSS-REFERENCES TO RELATED APPLICATION S This is a continuation-in-part of application Ser. No. 197,475, filed Nov. 10, 1971, now Pat. No. 3,759,927, which in turn is a continuation-in-part of application Ser. No. 183,694, filed Sept. 24, 1971, which in turn is a continuation-in-part of application Ser. No. 105,126, filed Ian. 8, 1971, now abandoned.

BACKGROUND OF THE INVENTION Pursuant to the discovery of the hypotensive N-[1-(2,3- dihydro-2-benzofuryl)-alkyl]-piperazines, described in my US. Pats. Nos. 3,459,860 and 3,470,185, and related 1- (2,3-dihydro-2-benzofuryl)-alkyl compounds with vasodilating activity, there was generated a new class of compounds herein described, which members surprisingly do not exhibit hypotensive effects but, instead, marked central nervous system depressant activity. Their spectrum of pharmacological properties is quite different from that exhibited by the substituted 1,3,8-triaza-spiro(4,5) decanes disclosed in US. Pat. No. 3,238,216, which still exhibit vasodila-ting activity.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 8-[l-(2,3-dihydro-2-benzofuryl)- alkyl]-1,3,8-triazaspiro(4,5)decanes, more particularly of those corresponding to Formula I wherein Ph is a 1,2-phenylene radical, each of R R and R is hydrogen or lower alkyl, each of alk and alk is lower alkylene separating the nitrogen atom from the spiro-carbon atom by two ring-carbon atoms, R, is hydrogen, an aliphatic, araliphatic or aromatic radical, R is two hydrogens, hydrogen and lower alkyl or oxo, and R is hydrogen, lower alkyl or lower hydroxyalkyl, of acyl derivatives, N-oxides, quaternaries or salts thereof, of corresponding pharmaceutical compositions and of methods for the preparation and application of these products, which are useful neuroleptics, for example, in the treatment or management of agitation, aggression, anxiety or hysteria in warm-blooded animals. Thus, when administered to them in effective dosages and suitable application forms, they facilitate their handling, e.g. during shipment, due to the reduction of their spontaneous motor activity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The 1,2-phenylene radical Pb in Formula I is unsubstituted or substituted by one or more than one, preferably by one or two of the same or of different substituents attached to any of the positions available for substitution. Such substituents are, for example, lower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl; free, etherified or esterified hydroxy, mercapto or lower hydroxyalkyl, preferably ot-hydroxyalkyl, such as lower alkoxy, alkylene dioxy, alkylmercapto, halogeno, lower (hydroxy, alkoxy, mono-, dior trihalo)-alkyl, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy; methylenedioxy; methylor ethylmercapto; fiuoro, chloro or bromo; (hydroxy, methoxy, chloro or trifiuoro)-methyl, 1- or Z-(hydroxy, methoxy 0r chloro)-ethyl or 1-hydroxy-2-methylpropyl; nitro; amino or di-lower alkylamino, e.g. dimethylamino or diethylamino; or acyl, such as lower alkanoyl, lower alkylsulfinyl or -sulfonyl, e.g. acetyl, propionyl or butyryl; methylor ethylsulfinyl or -sulfonyl. The term lower, referred to above or hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms.

Preferred radicals Ph are 1,2-phenylene, (lower alkyl)- 1,2-phenylene, (hydroxy)-1,2-phenylene, monoor di- (lower alkoxy)-1,2-phenylene, (lower alkylenedioxy)-l,2- phenylene, (lower alkylmercapto)-1,2-phenylene, (halogeno) 1,2 phenylene, (lower a-hydroxyalkyl)-1,2- phenylene, (trifluoromethyl) 1,2 phenylene, (nitro)- 1,2-phenylene, (amino)-1,2-phenylene, (di-lower alkylamino) 1,2 phenylene, (lower alkanoyl) 1,2 phenylene, (lower alkylsulfinyl)-l,2-phenylene or (lower alkylsulfonyl)-1,2phenylene.

Each ofthe radicals R R R R and R represent preferably hydrogen, but also lower alkyl, e.g. that mentioned above, especially methyl, or, in case of R hydrogen and lower alkyl, e.g. methyl.

The lower alkylene radicals alk, and alk stand preferably for 1,2-ethylene, but also for 1,2-propylene, 1,2- or 2,3-butylene.

An aliphatic radical R is, for example, lower alkyl, e.g. that mentioned above, lower alkenyl or alkynyl, e.g. allyl, methallyl, 2- or 3-butenyl; propargyl, 2- or 3- butynyl; lower cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl; 2-cyclopentenyl or -cyclohexenyl; cyclopropylmethyl, cyclobutylmethyl or 2-cyclopentylethyl; cyclopent 2 enylmethyl or cyclohex 3 enylmethyl.

An araliphatic or aromatic radical R is preferably represented by HPh-C,,H wherein Ph has the above-given meaning and n is an integer from 0 to 4, preferably 0 or 1.

A lower hydroxyalkyl radical R is preferably hydroxymethyl, 1- or 2-hydroxyethyl, but also, 1-, 2- or 3-hydroxypropyl or -butyl.

Acyl derivatives are preferably derived from (a) the compounds of Formula I, in which R, and/or R is hydrogen, or Ph or R contain hydroxy, mercapto or aminoand (b) lower aliphatic, araliphatic or aromatic carboxylic acids, such as those corresponding to the formulae wherein n and Ph have the acetyl, propionyl, pivaloyl, derivatives.

N-oxides and quaternaries are derived from (a) the compounds of Formula I, in which both R, and R are different from hydrogen and Ph is ditferent from (amino)- 1,2-phenylene; and the quaternaries (b) from lower alkyl halides, sulfates or sulfonates, e.g. lower alkylammonium chlorides, iodides, sulfates, methaneor p-toluenesulfonates.

Salts of the compounds of Formula I are preferably therapeutically acceptable acid addition salts derived, for example, from the inorganic or organic acids listed below.

The compounds of the invention exhibit valuable pharmacological properties, especially central nervous system depressant effects. This can be demonstrated in animal tests, using advantageously mammals, such as rats, mice, rabbits, cats, dogs and especially monkeys, as test objects. The compounds of the invention can be applied enterally or perenterally, e.g. orally, subcutaneously, intraperitoneally or intravenously, for example, within gelatin capsules, suspended in corn starch or in the form of aqueous solutions or suspensions respectively. The oral dosage may range in the lower animals, e.g. mice or rats, between about 0.1 and 200 mg./kg./day, preferably between about 1 and 50 mg./kg./day, and in the higher animals, e.g. dogs or monkeys, between about 0.1 and 10 mg./kg./day, preferably between about 0.3 and 2.5 mg./kg./day. Said compounds produce, for example, a quieting effect in mice, as demonstrated in the jiggle-cage or light-box test, where a reduction of their spontaneous motor activity is recorded after oral or subcutaneous doses as low as 2.5 mg./kg./day. At about 10 mg./kg./day orally, they antagonize for more than four hours the stimulating effects of amphetamine in rats, working (barpressing) in an operant electric shock avoidance situation. Analogously, they decrease at oral doses between about 0.1 and 10 mg./kg./day the lever-pressing avoidance responses of squirrel monkeys, i.e. the number of electric shocks taken by the animals increases with the dose applied (Sidman procedure). Intravenous administration of said compounds at a dose of about 2 mg./kg./day to rabbits induces a cataleptic-like state, from which the animals can be very easily aroused (unaltered righting reflex) and at doses of about 10 mg./kg./day i.v. no effect on the respiration is observed in anesthetized cats, but a depression of their flexor and patellar reflexes. Accordingly, the compounds of the invention are useful neuroleptics, for example, in the treatment or management of agitation, aggression or anxiety in warm-blooded animals, preferably mammals. They are also valuable intermediates of other preparations, preferably pharmacologically useful products.

Preferred compounds of the invention are those of Formula I, in which Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by up to two members of the group of lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, lower alkylmercapto, halogeno, lower (hydroxy, alkoxy, mono-, dior trihalo)-alkyl, nitro, amino, di-lower alkylamino, lower alkanoyl, lower alkylsulfinyl or lower alkylsulfonyl, each of R R and R is hydrogen or lower alkyl, each of alk and alk is lower alkylene separating the nitrogen atom from the spirocarbon atom by two ring-carbon atoms, R; is hydrogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower akyl, cycloalkenyl-lower alkyl or HPhC 'H wherein n is an integer from to 4, R is two hydrogens,

hydrogen and lower alkyl or oxo, and R is hydrogen, lower alkyl or hydroxy-lower alkyl, or a lower alkanoyl,

meaning given above, e.g. phenylacetyl or benzoyl HPh-lower alkanoyl or HPh-carbonyl derivative of said compounds in which R; and/or R is hydrogen or Ph or R contain hydroxy, mercapto or amino, the N-oxide or lower alkyl quaternaries of said compounds in which R and R are different from hydrogen and Ph is different from (amino)-1,2-phenylene, or therapeutically acceptable acid addition salts thereof.

Particularly useful are those compounds of Formula I, in which Ph is 1,2-phenylene, (lower alkyl)-1,2-phenylene, (hydroxy)-1,2-phenylene, monoor di (lower alkoxy)-1,2-phenylene, (lower alkylenedioxy) -1,2-phenylene, (lower alkylmercapto) l,2 phenylene, (halogeno) 1,2- phenylene, (lower a-hydroxyalkyl)-1,2-phenylene, (trifluoromethyl)-l,2 phenylene, (nitro) 1,2 phenylene, (amino) 1,2 phenylene, (di lower alkylamino) 1,2- phenylene, (lower alkanoyl)-1,2-phenylene, (lower alkylsulfinyl)-1,2 phenylene or (lower alkylsulfonyl) 1,2- phenylene, each of R R and R is hydrogen or lower alkyl, each of alk and alk is lower alkylene separating the nitrogen atom from the spirocarbon atom by two ring-carbon atoms, R; is hydrogen, lower alkyl, 3 to 7 ring-membered cycloalkyl or cycloalkyl-lower alkyl or H-PhC H wherein n is an integer from 0 to 4, R is two hydrogens, hydrogen and lower alkyl or 0x0 and R is hydrogen, lower alkyl or hydroxy-lower alkyl, or a lower alkanoyl derivative of said compounds in which R, and/or R is hydrogen or Ph or R contain hydroxy, mercapto or amino, the N-oxide or lower alkyl quaternaries of said compounds in which R and R are diiferent from hydrogen and Ph is different from (amino)-l,2-phenylene, or therapeutically acceptable acid addition salts thereof.

More preferred are compounds of Formula II in which R-, is hydrogen, lower alkyl, hydroxy, lower alkoxy, halogeno, lower a-hydroxyalkyl, trifluoromethyl or lower alkanoyl, each of R R and R is hydrogen or lower alkyl, R is lower alkyl, 3 to 7 ring-membered cycloalkyl or R -phenyl, and R is hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkanoyl, or lower alkyl quaternaries of said compounds in which R is lower alkyl or hydroxy-lower alkyl, or therapeutically acceptable acid addition salts thereof.

Particularly valuable are those compounds of Formula II, in which R, is hydrogen, alkyl, hydroxy, alkoxy, halogeno, a-hydroxyalkyl, trifluoromethyl or alkanoyl, each of R R and R is hydrogen or methyl and R is methyl, cyclohexyl or R -phenyl, R is hydrogen, methyl, hydroxymethyl or acetyl, and alkyl, alkoxy or alkanoyl contains up to 4 carbon atoms, or therapeutically acceptable acid addition salts thereof.

Especially valuable are the compounds of Formula II, in which R, is hydrogen, methyl, methoxy, fluoro, chloro, l-hydroxyethyl, trifluoromethyl or acetyl, each of R R R and R is hydrogen or methyl and R is R -phenyl, and of these especially the 1-phenyl-4-oxo-8-[S-methoxyor 5-(1-hydroxyethyl)-2,3-dihydro-2 benzofurylmethyH- 1,3,8-triazaspiro(4,5)decane, or a therapeutically acceptable acid addition salt thereof, more particularly the optically levorotatory forms thereof, which exhibit outstanding effects in the above-described test systems, especially the Sidman procedure.

The compounds of the invention are prepared according to known methods, for example, by:

(a) Condensing a reactively converted 1-(2,3-dihydro 2-benzofuryl)-alkanol or an -alkylamine with an 8-unsubstituted 1,3,8-triazaspiro(4,5)decane or a reactively converted 5-bis-(2-hydroxyalkyl) 2,3 dihydro-4-imid azolone or a metal salt of said amines or imines, e.g. compounds of the formulae in which X is reactively esterified hydroxy or amino and Y is imino or two reactively esterified hydroxies, both X and Y together contain but one nitrogen atom or (b) Condensing a 1-[1(2,3-dihydro-2-benzofuryl)-alkyl]-4-aminohexahydroisonicotinic acid amide or nitrile with a reactive derivative of a lower alkanal, formic or carbonic acid, eg, compounds of the formulae CHI-R1 CH-Ra alk Z 0 Rz al NHR in which Z is CONHR or CN and Z is oxo, hydrogen and amino or two reactively converted hydroxy or amino groups, both Z and R together contain but one 0x0, or (c) Reducing a dehydroand/ or hydroxy-derivative of an 8-[1-(2,3 dihydro 2 benzofuryl)alkyl]-1,3,8-triazaspiro(4,5)decane, e.g. such of the formula CH-Rz w 81k in which W is free or reactively converted if at least one double bond extends from the 2-carbon atoms and, if desired, converting any resulting compound into another compound of the invention.

A reactively converted hydroxy group in the above starting materials is preferably a hydroxy group esterified with a strong mineral or sulfonic acid, e.g. sulfuric, methane-, ethane-, benzene-, p-tolueneor camphorsulfonic acid, but preferably that of a hydrohalic acid, e.g. hydrochloric or hydrobromic acid. Z may also represent hydroxy groups etherified with lower alkanols or glycols, e.g. methanol, ethanol or ethyleneglycol. In case it is reactively converted amino, eg if R is oxo, Z may represent, for example, two imidazolyl groups. Metal salts of said amines or imines are preferably alkali metal, e.g. lithium, sodium or potassium salts.

The chemical processes of the present invention are carried out according to standard methods, e.g. in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or reducing agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or super-atemospheric pressure. Condensing agents are advantageously used in the process mentioned under items (a) and (b). In case reactive esters or acid derivatives respectively are used, the condensing agents are preferably basic agents, for example, alkali or alkaline earth metal carbonates, hydroxides or lower alkoxides, such as sodium, potassium or calcium carbonate, sodium or potassium hydroxide, methoxide or ethoxide, but also organic nitrogen bases, such as aliphatic or aromatic tertiary amines, such as trilower alkylamines, e.g. triethylamine; pyridine or collidine. In case acetals are used in the condensation shown under item (b), acidic agents are advantageously applied, e.g. the strong mineral or sulfonic acids mentioned above. A preferred condensation is that in which Z=C=R is formamide, which has to be applied in at least 2 mole equivalents, in order to obtain the compounds of Formula I, ammonia and carbon dioxide. Said nitriles are advantageously reacted with formaldehyde and the resulting Schiffs base treated with a strong base, such as an alkali metal lower alkoxide, e.g. sodium methoxide, to yield said products I.

The reduction according to item (c) is advantageously performed with the use of catalytically activated or nascent hydrogen, such as hydrogen in the presence of platinum, palladium or nickel catalysts or generated from alcohols or weak acids and metals, e.g. lower alkanols and light metals, such as alkali metals or amalgams thereof, or lower alkanoic acids and heavy metals, such as zinc, cadmium or iron. Also reducing agents may be used, advantageously, complex light metal hydrides, such as alkali metal aluminum or borohydrides, e.g. lithium aluminum hydride or sodium borohydride, if desired, in combination with a Lewis acid, e.g. aluminum chloride.

The compounds of the invention so obtained can be converted into each other according to known methods. For example, resulting compounds containing a primary or secondary amino group, can be reacted with a reactive ester of a corresponding alcohol, eg a lower alkanol, or can be acylated, for example, with a reactive functional derivative of a corresponding acid, such as a halide or anhydride thereof. Resulting acyl derivatives, e.g. esters or amides, can be hydrolyzed, for example, with the use of acidic or alkaline hydrolyzing agents, and ketones or amides also reduced to the corresponding a-hydroxyalkyl 1,2-phenylene or lower alkylamino or -imino compounds respectively, for example, with the use of complex light metal hydrides, eg sodium borohydride or lithium aluminum hydride respectively. Finally, resulting tertiary bases can be converted into N-oxides, preferably with the use of hydrogen peroxide or percarboxylic acids, such as peracetic or perbenzoic acid, or they can be quaternized, for example, with the use of lower alkyl halides or sulfonates, e.g. chlorides, bromides, iodides or p-toluenesulfonates.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with a kalies or ion exchangers. Free bases that are obtained can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically acceptable salts. Such acids are, for example, mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the invention, for example, the picrates, can also be used for purification of the bases obtained: the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. For example, the amines mentioned above can be used in the form of their alkali metal salts. Mainly, those starting materials should be used in the process of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting material used is known, or if new, may be prepared according to the methods illustrated by the examples herein or the literature cited. The 1-(2,3-dihydro- 2-benzofuryl) alkanol derivatives or -alkylamines, as well as the 1,3,8-triazaspiro(4,5)decanes are described in the patents cited in the beginning. The -bis-(2-hydroxyalkyl)- 2,3-dihydro-4-imidazolones are analogously prepared as the latter, but choosing instead of the initial 4-piperidone, the corresponding open-chain free or esterified dihydroxyalkanone, e.g. l,5-dihydroxy-3-pentanone. This is reacted according to Strecker with ammonia or the corresponding amine and hydrocyanic acid, the resulting a-aminonitrile hydrolyzed to the corresponding amide, which is ringclosed analogous to the process shown under item (b). The hexahydroisonicotinamides shown thereunder are analogously prepared from l-benzyl or 2,3-dihydro-2-benz0- furylalkyl)-4-piperidones according to the Strecker or Tiemann syntheses, debenzylating any amide or nitrile by hydrogenation and processing the resulting l-unsubstituted amide or nitrile analogous to (a). A similar condensation is applied for the preparation of the compounds mentioned under item (6). The double bond is advantageously introduced into the reactants, whereupon a condensation is performed with the dehydro-derivatives of the compounds shown under item (a). Said dehydro-spiroreactants are advantageously obtained by a ring-closing condensation analogous to (b) but using, instead of the lower alkanal derivatives, reactive lower alkanoic acid derivatives, e.g. lower alkyl orthoesters or iminoesters. Finally the compounds with are obtained by the addition of Z-benzofurane-carboxaldehydes or -alkanones, or -2,3-dihydro derivatives thereof, to 8-unsubstituted 1,3 ,8-triazaspiro (4,5 decanes.

Starting materials or final products that are mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example by separation of diastereomeric salts or esters thereof, e.g. by the fractional crystallization of dor l-tartrates, -maleates, -mandelates, -N-acetylphenylalaninates or -camphorsulfonates, and reconverting the diastereomeric salts or esters into the free antipodes, or using said ester-intermediates direct in reaction (a).

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/ or polyvinylpyrrolidone, if desired, ((1) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners, Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvant, such as preserving, stabilizing, Wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Said therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.

Preferred compositions for veterinary use are the parenterally, e.g. intravenously or intramuscularly, applicable solutions or suspensions. They may be applied prior to treating or causing painful conditions in the most preferred dosage range of about 0.3 to 2.5 mg./kg./day

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight.

Example 1 The mixture of 3.7 g. of Z-bromomethyl-5-methoxy-2,3- dihydrobenzofuran, 3.6 g. of 1-phenyl-4-oxo-1,3,8-triazaspiro(4,5)decane, 6 g. of anhydrous sodium carbonate and 50 ml. of 2-propanol is refluxed for three days. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is crystallized by agitating vigorously with a mixture of 50 ml. of diethyl ether and 50 ml. of water. The product is recrystallized twice from ethanol to afford the 1-phenyl-4-oxo-8-(5-methoxy-2,3-dihydro-2- benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane of the formula CHaO- j g NH CH \0/ Q melting at 191-192.

The hydrochloride salt thereof is prepared by adding 6 N ethanolic hydrogen chloride to an acetone solution of the above free base. The hydrochloride crystallizes out and melts at 290 with decomposition.

Example 2 In an analogous manner to Example 1, 2.8 g. of 2- bromomethyl-2,3-dihydrobenzofuran, 3.0 g. of l-phenyl- 4-oxo-1,3,8-triazaspiro(4,5)decane and 6 g. of anhydrous sodium carbonate in 40 ml. of 2-propanol are refluxed for three days which affords on recrystallization from acetoneethanol the 1-phenyl-4-oxo-8-(2,3-dihydro-2-benzofurylrzrbesthyl)-1,3,8-triazaspiro(4,5)decane, melting at 202- Example 3 2.7 g. of 2-bromomethyl -5 fluoro 2,3 dihydrobenzofuran, 2.7 g. of 1 phenyl 4 oxo 1,3,8 triazaspiro(4,5)decane and 5 g. of anhydrous sodium carbonate in 45 ml. of 2-propanol are treated as previously described in Example 1 to give the 1-phenyl-4-oxo-8-(5- fluoro 2,3 dihydro 2 benzofurylmethyl) 1,3,8 triazaspiro (4,5)decane, melting at 188-191 on recrystallization from ethanol.

The starting 2-bromomethyl 5 fluoro 2,3 dihydrobenzofuran is prepared as follows:

The mixture of g. of 4-fluorophenol, 300 ml. of acetone, 160 g. of potassium carbonate and g. of allyl bromide is refluxed for 8 hours and allowed to stand overnight. The mixture is diluted with 600 ml. of water and the resulting layers separated. The aqueous layer is extracted with 2 x 450 ml. of methylene chloride. The combined organic extracts are washed with 225 ml. of 10% aqueous sodium hydroxide, dried, filtered and the filtrate evaporated to give the 1-allyloxy-4-fluorobenzene.

60 g. thereof are heated under a nitrogen atmosphere to an internal temperature of 220 for 2 hours. On cooling, there is aiforded the 2-allyl-4-fluorophenol.

The mixture of 60 g. thereof and 102 g. of acetic anhydride is refiuxed for 3 hours. The acetic acid formed is removed under reduced pressure and the residue is distilled to afford the l-acetoxy 2 allyl 4 fluorobenzene, boiling at 1l8l21/14 mm. Hg.

The solution of 42 g. of bromine in 120 ml. of carbon tetrachloride is added dropwise to the solution of 51 g. of the above acetylated phenol in 150 ml. of carbon tetrachloride. The reaction mixture is stirred for 1 /2 hours after the addition and then treated with 60 ml. of saturated aqueous sodium carbonate and 100 ml. of water. The organic layer on separation is dried, filtered and evaporated under reduced pressure to give the 1,2-di-bromo-3- (2-acetoxy-5-fiuorophenyl propane.

The solution of 15 g. of sodium methoxide in 250 ml. of ethanol is added dropwise to the solution of 90 g. of the above dibromopropane in 125 ml. of ethanol. The reaction mixture is refluxed for 2 hours, filtered and the filtrate evaporated under reduced pressure. The residue is diluted with water and extracted with methylene chloride. The methylene chloride extract is dried and filtered; the filtrate is evaporated. The residue is distilled to afford the 2-bromomethyl 5 fluoro 2,3 dihydrobenzofuran, boiling at 135139/15 mm. Hg.

Example 4 The mixture of 1.1 g. of 2-bromomethyl-5-rnethoxy-1,2- dihydrobenzofuran, 1.1 g. of l-cyclohexyl 4 oxo-1,3,8- triazaspiro(4,5)decane, 3 g. of sodium carbonate and 25 ml. of 2-propanol is refluxed for 3 days. The salts are filtered off and the filtrate evaporated under reduced pressure. The residue is treated with a mixture of 50 ml. of diethyl ether and 50 ml. of water. The ether layer is separated and extracted with aqueous citric acid. The combined acid fractions are made basic with ammonium hydroxide and extracted with diethyl ether. The ether extracts are dried and evaporated. The residue is recrystallized from ethanol to give the l-cyclhexyl-4-oxo- 8-(5-methoxy 2,3 dihydro 2 benzofurylmethyl)- 1,3,8-triazaspiro(4,5)decane, melting at 155-156".

Example 5 To the solution of 50 g. of d,l-l-phenyl 4 oxo-8-(5- methoxy 2,3 dihydro 2 benzofurylmethyl) 1,3,8- triazaspiro(4,5)decane (obtained according to Example 1) in 1.8 lt. of acetone, the solution of 26.4 g. of N-acetyll-phenylalanine in 350 ml. of acetone is added while stirring and the mixture concentrated to about 1.5 It. It is allowed to stand overnight in the refrigerator, and the precipitate formed filtered off, to yield the salt A, mp. 103-105 (dec.). The mother liquor is further concentrated to about 800 ml., and the precipitate formed in the cold filtered off, to yield the salt B, m.p. 90-105 31 g. of the salt A is recrystallized from 325 ml. of ethanol containing 6 ml. of water, 26 g. of the recovered material recrystallized from 325 ml. of ethanol containing 4 ml. of water and 24.5 g. of the recovered material recrystallized from 450 ml. of ethanol. The purified salt is taken up in water, the mixture made basic with aqueous ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the l-l-phenyl-4-oxo-8-(5- methoxy 2,3 dihydro 2 benzofurylmethyl)-l,3,8-triazaspiro(4,5)decane, melting at 185188, [a] =-12.4 (chloroform) The salt B is taken up in water, the mixture made basic with aqueous ammonia and extracted with chloroform. The extract is dried and evaporated. 18.1 g. of the residue are taken up in 450 ml. of acetone and the solution combined with that of 9.55 g. N-acetyl-d-phenylalanine in 180 ml. of acetone. The mixture is concentrated to about 500 ml. and 21 g. of the precipitate formed in the cold recrystallized first from 400 ml. of ethanol containing 2 ml. of water. 17 g. of the recovered material is recrystallized from 300 ml. of ethanol and the resulting salt converted into the free base as shown above, to yield the d-lphenyl 4 0x0 8 (S-methoxy 2,3 dihydro-Z-benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane, melting at 184-186", [a] =+12.4 (chloroform).

Example 6 To the solution of 3 g. of either and d,lor the H- phenyl-4-oxo-8-(5-methoxy 2,3 dihydro-2-benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane in ml. of acetone and 30 ml. of ethanol, 0.8 ml. of methanesulfonic acid are added, followed by 20 ml. of water and 200 ml. diethyl ether while stirring. The precipitate formed is filtered ofl and recrystallized from water, to yield either the d,lor the l-1-phenyl-4-oxo-8-(5-methoxy-2,3-dihydro- 2 benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane methanesulfonate hemihydrate, both melting at 188190.

Example 7 The mixture of 6.6 g. of 2-bromomethyl 7 methoxy- 2,3-dihydrobenzofuran, 6.3 g. of 1-phenyl-4-oxo-1,3,8-triazaspiro(4,5)decane, 12 g. of sodium carbonate and 100 ml. of 2-propanol is refluxed for 3 days while stirring. After cooling, it is filtered, the filtrate evaporated under reduced pressure and the residue taken up in diethyl ether. The solution is shaken with 5% hydrochloric acid. the suspension formed filtered, the precipitate suspended in water and the mixture made basic with aqueous ammonia. It is extracted with chloroform, the extract dried, filtered, evaporated and the residue recrystallized from ethanol, to yield the 1-phenyl-4-oxo-8-(7-methoxy-2,3-dihydro 2 benzofurylmethyl) 1,3,8 triazaspiro(4,5) decane, melting at 170.

Example 8 The mixture of 12.5 g. of a 2:1 composition of 2-bromomethyl 4- or 6-methoxy-2,3-dihydrobenzofuran, 12 g. of 1-phenyl-4-oxo-1,3,8-triazaspiro(4,5 )decane, 25 g. of sodium carbonate and 200 ml. of 2-propanol is refluxed for 3 days while stirring. After cooling, it is filtered, the filtrate evaporated and the residue taken up in diethyl ether. The solution is shaken with 5% hydrochloric acid, the aqueous solution made basic ammonia and extracted with diethyl ether. The extract is dried, evaporated and the residue chromatographed on silica gel. The column is eluted with benzene-methanol (9:1), to yield a first eluate containing the 1-phenyl-4-oxo-8-(4-methoxy-2,3-dihydro- 2-benzofurylmethyl)-1,3,8-triazaspiro-(4,5 decane, showing in the LR. spectrum bands at 3193, 1695, 1590, 1195, 804, 749 and 690 cmr followed by the 1-phenyl-4-oxo- 8 (6 methoxy-2,3-dihydro-Z-benzofurylmethyl) 1,3,8- triazaspiro-(4(5)decane, having a similar IR. spectrum, but the band at 804 CIll." is missing, whereas a new band at 785 cm. appears. Both isomers have in the thin layer chromatogram on silica gel with the same eluent a R =6.0 and 7.0 respectively.

The starting material is prepared as follows: The mixture of 100 g. of 3-methoxyphenol, 70 ml. of allyl bromide, g. of potassium carbonate and 200 ml. of acetone is refluxed for 8 hours while stirring. It is diluted with water and extracted with 500 ml. of diethyl ether. The extract is washed with 5% aqueous sodium hydroxide and water, dried and evaporated, to yield the 3-allyloxyanisole.

It is taken up in 200 ml. of N,N-dimethylaniline and the mixture refluxed for 2 hours. After cooling, the mixture is poured onto crushed ice and acidified with hydrochloric acid. It is extracted with diethyl ether, the extract washed with water and shaken with 5% aqueous sodium hydroxide. The aqueous layer is acidified with hydrochloric acid and extracted with diethyl ether. The extract is dried, evaporated and the residue refluxed with ml. of acetic anhydride for 3 hours. The mixture is evaporated under reduced pressure, the residue distilled and the frac tion boiling at 156158/ 15 mm. Hg collected, to yield a 2:1 mixture of 3-acetoxy-4-allylanisole and 3-acetoxy 2-allylanisole.

To the solution of 53 g. thereof in ml. of carbon tetrachloride, 41 g. of bromine in 50 ml. of carbon tetrachloride are added dropwise during 1 hour while stirring and keeping the temperature below 25. The mixture is washed with aqueous sodium bicarbonate, dried and evaporated. The residue is taken up in 75 ml. of ethanol and to the solution that of 14.5 g. of sodium methoxide in 50 ml. of ethanol is added during /2 hour while stirring. The mixture is refluxed for 1 hour, cooled, filtered, and the filtrate concentrated under reduced pressure. The concentrate is diluted with water, extracted with chloroform, the extract dried and evaporated, to yield a 2:1 mixture of the 2-bromoethyl-4- or 6-methoxy-2,3-dihydrobenzofuran, which is used as such without further purification.

Example 9 The mixture of 3.1 g. of 2-bromomethyl-2-methyl-5- methoxy-2,3-dihydrobenzofuran, 2.9 g. of 1-phenyl-4-oxo- 1,3,8-triazaspiro(4,5)decane, 6 g. of sodium carbonate and 50 ml. of 4-methyl-2-pentanone is refluxed for 1 week while stirring. It is cooled, filtered, and the filtrate washed with Water and 5% hydrochloric acid. The combined aqueous solutions are made basic with ammonia and extracted with chloroform. The extract is dried, evaporated under reduced pressure, and the residue chromatographed on silica gel. The column is eluted with chloroform-diethylamine 9:1, to yield the 1-phenyl-4-oxo-8-(5-methoxy-2- methyl 2,3 dihydro-2-benzofurylmethyl)-1,3,8-triazaspiro(4,5)decane, showing in the thin layer chromatogram with the same stationary and mobile phase a R -=60 The hydrochloride thereof melts at 280-282 (dec.).

The starting material is prepared as follows: The mixture of 100 g. of 4-methoxyphenol, 73 g. of 3-chloro-2- methylpropene, 117 g. of potassium carbonate and 200 ml. of acetone is refluxed for 12 hours while stirring. After cooling, it is diluted with water and extracted with diethyl ether. The extract is washed with 5% aqueous sodium hydroxide, dried and evaporated under reduced pressure, to yield the 4-methallyloxyanisole.

It is diluted with an equal volume of N,N-dimethylaniline and the mixture refluxed for 6 hours. After cooling, it is poured onto ice and the mixture acidified with hydrochloric acid. It is extracted with diethyl ether, the extract washed with water, dried and evaporated under reduced pressure. The residue is taken up in petroleum ether and the mixture extracted With a solution prepared from 35 g. of potassium hydroxide, ml. of water and 100 ml. of methanol. The aqueous phase is diluted with water, acidified with hydrochloric acid, extracted with diethyl ether, the extract dried and evaporated, to yield the 2-methallyl-4-methoxyphenol.

66 g. thereof are added to the solution of 122 g. of mercuric chloride in 1.3 lt. of water, and the mixture stirred at room temperature overnight. It is filtered and the residue recrystallized from ethanol, to yield the 5- methoxy-Z-methyl-Z,3-dihydro-2-benzofurylmethyl mercuric chloride, melting at 70 To the suspension of 44.5 g. thereof in 150 ml. carbon tetrachloride, the solution of 5.75 ml. of bromine in 50 ml. of carbon tetrachloride is added dropwise while stirring at 05. After 6 hours, the mixture is filtered and the filtrate evaporated, to yield the 2-bromomethyl-2-methyl5-methoxy-2,3-dihydrobenzofuran.

Example 10 The mixture of 1 g. of 1-phenyl-4-oxo-8-(S-methoxy- 2,3 dihydro-2-benzofurylmethyl) -1,3 ,8-triazaspiro (4,5 dec-2-ene, 0.1 g. of 10% palladium on charcoal and 50 ml. of glacial acetic acid is hydrogenated at room temperature and 2.7 atm. until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate concentrated under reduced pressure, the concentrate diluted with water and made basic with ammonia. The precipitate formed is filtered otf and recrystallized from ethanol, to yield the l phenyl-4-oxo-8-(5-methoxy-2,3-dihydro-2-benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane, melting at 191-192; it is identical with that obtained according to Example 1.

The same compound can also be obtained by the analogous reduction of the 1-phenyl-4-oxo-8-(S-methoxy- 2-benzofurylmethyl l ,3,8-triazaspiro (4,5 decane.

The starting material is prepared as follows:

(a) The mixture of 6 g. of 1-benzyl-4-phenylaminohexahydroisonicotinamide, 2 g. of 10% palladium on charcoal, ml. of glacial acetic acid and 10 ml. of water are hydrogenated at 2.7 atm. and 60 until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate evaporated under reduced pressure and the residue taken up in water. The mixture is made basic with ammonia, extracted with chloroform, the extract dried and evaporated. The residue is recrystallized from ethanol, to yield the 4-phenylamino-hexahydroisonicotinamide, melting at 209210.

The mixture of 1.9 g. thereof, 2.1 g. of 2-bromomethyl- 5-methoxy-2,3-dihydrobenzofuran, 4 g. of sodium carbonate and 200 ml. of 2-propanol is refluxed for 4 days, cooled, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in a mixture of 50 ml. of diethyl ether and 50 ml. of water and the precipitate formed on standing filtered off. It is recrystallized from ethanol, to yield the 1-(5-methoxy-2,3-dihydro-2-benzofurylmethyl)-4-phenylamino hexahydroisonicotinamide, melting at 150. The mixture of 2 g. thereof, ml. of trimethyl orthoformate and 25 mg. of p-toluenesulfonic acid is refluxed for 24 hours in a Soxhlet apparatus, passing the condensate over a molecular sieve removing methanol. The mixture is evaporated and the residue triturated with a small amount of methanol, to yield the l-phenyl-4- oxo-8-(5-methoxy-2,3-dihydro 2 benzofurylmethyl)-1, 3,8-triazaspiro (4,5 dec-Z-ene.

(b) To the solution of 17.7 g. of 6-methoxycoumarin in 60 ml. of chloroform, 5.5 ml. bromine in 10 ml. of chloroform are added dropwise while stirring at room temperature. After stirring overnight, 20 ml. of 20% aqueous sodium sulfite are added dropwise, the organic phase separated and the aqueous layer washed with chloroform. The combined organic phase is washed with water, dried, filtered and evaporated under reduced pressure, to yield the 3,4 dibromo-6-methoxy-3,4-dihydrocoumarin.

The solution of 27.3 g. thereof in 20 ml. of ethanol is added portionwise to the mixture of 50 g. potassium hydroxide and 75 ml. of ethanol while stirring at about 15. The mixture is refluxed for 2% hours, concentrated and the concentrate diluted with Water. It is acidified with 6N hydrochloric acid, the precipitate formed filtered off, washed with water, recrystallized first from aqueous ethanol and then from ethanol, to yield the S-methoxy-Z- benzofurancarboxylic acid, melting at 174-178.

The solution of 3.7 g. thereof in 50 ml. of tetrahydrofuran and 50 ml. of diethyl ether is added to the suspension of 1.8 g. of lithium aluminum hydride in 25 ml. of diethyl ether While stirring at room temperature. After stirring overnight, 1.8 ml. of water, 3.6 ml. of 12% aqueous sodium hydroxide and 5.4 ml. of water are added, the mixture filtered and the filtrate evaporated under reduced pressure. The residue is taken up in diethyl ether, the solution Washed with saturated aqueous sodium bicarbonate and water, dried and evaporated, to yield the 2- hydroxymethyl-S-methoxybenzofuran, showing in the LR. spectrum bands at 3250, 1600, 1205, 1160, 1010 and 850 cm.

To the solution of 1.5 g. thereof in 50 ml. of diethyl ether, 0.28 ml. of phosphorus tribromide are added during 5 minutes while stirring at 70. The mixture is allowed to warm to room temperature and stirred for 3 hours. It is poured over'ice, the organic phase Washed with saturated aqueous sodium bicarbonate and water, dried and evaporated, to yield the 2-bromomethyl-5-methoxybenzofuran.

The mixture of 3.8 g. thereof, 3.6 g. of 1-phenyl-4- oxo-1,3,8-triazaspiro(4,5)decane, 2 g. of sodium carbonate and 210 ml. of 4-methyl-2-pentanone is refluxed for 3 days while stirring. After cooling, it is filtered, the filtrate washed with water and shaken with hydrochloric acid. The precipitate formed is filtered off and washed with water, to yield the 1-phenyl-4-oxo-8-(5-methoxy-2- benzofurylmethyl)-1,3,8 triazaspiro(4,5)decane hydrochloride, melting at 260-265 It is taken up in water, the mixture made basic with ammonia, extracted with diethyl ether and the extract evaporated, to yield the corresponding free base.

Example 11 The mixture of 6 g. of 1-(5-methoxy-2,3-dihydro-2- benzofurylmethyl)-4-phenylamino hexahydroisonicotinamide and 20 ml. of formamide is heated to 170 for 12 hours, cooled and diluted with 100 ml. of water. The mixture is extracted twice with 50 ml. of chloroform, the extract dried and evaporated under reduced pressure. The residue is recrystallized from ethanol, to yield the l-phenyl-4-oxo-8-(5-methoxy-2,3-dihydro 2 benzofurylmethyl)-1,3,8-triazaspiro(4,5)decane melting to 190-192"; it is identical with that obtained according to Example 1.

Example 12 The mixture of 15.5 g. of 2-bromomethyl-5-methoxy- 2,3-dihydrobenzofuran, g. of 4-oxo-l,3,8-triazaspiro (4,5)decane, 20 g. of sodium carbonate and 100 ml. of isopropanol is refluxed for 3 days while stirring. It is cooled, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in methylene chloride and the solution extracted with 5% methane sulfonic acid. The aqueous phase is made basic with ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the 4-oxo-8-(5-methoxy-2,3-dihydro- 2-benzofurylmethyl)-1,3,8-triazaspiro( 4,5 decane, showing in the LR. spectrum bands at 3158, 1700, 1600 and 1204 cmr The starting material is prepared as follows: To the mixture of 38 g. of l-benzyl-4-piperidone, 15.5 g. of ammonium acetate and 120 ml. of acetic acid, the solution of 14.3 g. of potassium cyanide in 40 ml. of water is added while stirring at 45. After stirring for 24 hours at room temperature, the mixture is poured onto 200 g. of ice and 260 ml. of saturated aqueous ammonia. It is extracted with chloroform, the extract dried and evaporated, to yield the 4-amino-l-benzyl-hexahydroisonicotinonitrile.

The mixture of 10 g. thereof and 100 ml. of 80% sulfuric acid is heated to 70 for 10 minutes while stirring. It is cooled, made basic with ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the 4-amino-l-benzyl-hexahydroisonicotinamide.

The mixture of 20 g. thereof and 60 ml. of formamide is heated to 170 for 12 hours While stirring. After cooling, it is poured into 300 ml. of water and the mixture extracted with chloroform. The extract is dried and evaporated, to yield the 8-benzyl-4-oxo-1,3,8-triazaspiro- (4,5 decane.

20 g. thereof are dissolved in 200 m1. of 90% acetic acid and the solution hydrogenated at 55 over 5 g. of 10% palladium on charcoal until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate evaporated and the residue taken up in 30 ml. of water. The solution is made basic with ammonia, extracted with chloroform, the extract dried and evaporated, to yield the 4-oxo-1,3,9-triazaspiro (4,5 decane.

Example 13 To the solution of 0.668 g. of l-2-(tosyloxymethyl)-S- methoxy-2,3-dihydrobenzofuran in 5 ml. of dimethylformamide, 0.475 g. of 1-phenyl-4-oxo-1,3,8-triazaspiro(4,5) decane and 0.15 g. sodium carbonate are added and the mixture stirred for six hours at 110. It is cooled, diluted with water and filtered two hours thereafter, the residue dried and recrystallized from benzene, to yield the H- phenyl-4-oxo 8 (5-methoxy-2,3-dihydro-2-benzofuryl- 14 methyl) 1,3,8-triazaspiro(4,5)decane melting at 188 190, [a] =1l.9 (chloroform); it is identical with that obtained according to Example 5.

The starting material is prepared as follows: To the solution of 0.97 g. of d,l-5-methoxy-2,3-dihydro-2-benzofurancarboxylic acid in 50 ml. of diethyl ether, 0.7 g. of l-amphtamine are added while stirring. The precipitate formed is filtered off and washed with diethyl ether, to yield the corresponding salt melting at 134-142". It is taken up in 125 ml. of hot acetone and the solution allowed to cool to room temperature during 2 /2 hours. The precipitate formed is filtered off, washed with acetone and again dissolved in 60 ml. of hot acetone. The precipitate formed after three hours cooling is again filtered off, to yield the corresponding d-salt melting at 153-162".

All the mother liquors obtained are concentrated to a volume of 60 ml. and the solution allowed to cool to room temperature for three hours. The precipitate formed is filtered olf and recrystallized once from acetone, to yield the corresponding l-salt melting at 150l65.

Both salts obtained are taken up in the minimum amount of 6N hydrochloric acid and the solution obtained extracted with diethyl ether. The extract is washed with water and saturated aqueous sodium chloride, dried and evaporated, to yield the:

(a) d-5-rnethoxy-2,3-dihydro 2 benzofurancarboxylic acid, [a] =-|37 (chloroform) (b) the l-antipode thereof, [a] =38 (chloroform).

To the solution of 0.68 g. of said d-acid in 25 ml. of tetrahydrofuran, 0.15 g. of lithium aluminum hydride is added and the mixture refluxed for one hour. After cooling 0.15 ml. of water, 0.3 ml. of 12% aqueous sodium hydroxide and 0.45 ml. of water are added, the mixture filtered and the filtrate evaporatedunder reduced pres sure. The residue is taken up in benzene, the solution filtered and the filtrate evaporated under reduced pressure, to yield the l-2-hydroxymethyl-5-methoxy-2,3-dihydrobenzofuran, [a] =49 (chloroform).

Analogously, the l-acid is reduced to yield the corresponding d-alcohol, [a] =}-45 (chloroform).

To the solution of 0.5 g. of said l-alcohol in 5 ml. of pyridine, 0.75 g. of p-tolnenesulfonyl chloride are added and the mixture stirred overnight at room temperature. Thereupon 5 ml. of water are added and the mixture stirred for 10 minutes. It is further diluted with water, extracted with benzene, the extract washed with 5N hydrochloric acid, water and saturated aqueous sodium chlo ride, dried, evaporated under reduced pressure and the residue triturated with diethyl ether, to yield the L2- (tosyloxymethyl) 5 methoxy-Z,3-dihydrobenzofuran melting at 81.

Example 14 The mixture of 10 g. of 1-phenyl-5-bis-(2-tosyloxyethyl)-2,3-dihydro-4-imidazolone, 3,2 g. of Z-aminomethyl-S-acetyl-Z,3-dihydrobenzofuran, 20 g. of sodium carbonate and 50 ml. of isopropanol is refluxed for three days while stirring. It is filtered hot, the filtrate evaporated under reduced pressure and the residue stirred with a mixture of 50 ml. of water and 50 ml. of diethyl ether. The precipitate formed is filtered off and recrystallized from acetone, to yield the 1-phenyl-4-oxo-8-(5-acetyl-2,3-dihydro 2 benzofurylmethyl)-1,3,8-triazaspiro(4,5)decane, melting at 166-168.

The starting material is prepared as follows: To the stirred solution of 20 g. of 1,5-dihydroxy-3-pentanone and 15.8 g. of aniline in 70 ml. of acetic acid, the solution of 11.1 g. of potassium cyanide in 30 ml. of Water is added dropwise while stirring at 45. After allowing the mixture to stand for one day at room temperature, it is poured over 100 g. of ice and extracted with chloroform. The extract is dried and evaporated, to yield the a-phenylamino-w (2-hydroxyethyl) -hydroxybutyro nitrile.

The mixture of 20 g. thereof and g. of 80% sulfuric acid is heated to 70 for ten minutes and poured onto ice.

1 The mixture is made basic with ammonia, extracted with chloroform, the extract dried and evaporated, to yield the corresponding amide.

The mixture of 30 g. thereof and 60 ml. of formamide is stirred at 170 for 12 hours. After cooling it is diluted with water, extracted with chloroform, the extract dried and evaporated. The residue is taken up in 100 ml. of pyridine, the solution cooled to 5 and 34 g. of p-toluenesulfonyl chloride slowly added while stirring at said temperature. After stirring overnight at room temperature, 300 ml. of water are added slowly and the mixture extracted with chloroform. The extract is washed with 5% hydrochloric acid and water, dried and evaporated under reduced pressure, to yield the l-phenyl-S-bis-(2-tosyloxyethyl)-2,3- dihydro-4-imidazolone.

Example 15 The mixture of 13.2 g. of 2-bromomethyl-5-methoxy- 2,3-dihydrobenzofuran, g. of 3-methyl-2,3-dioxo-1,3,8- triazaspiro(4,5)decane, 20 g. of sodium carbonate and 200 ml. of isopropanol is refluxed for three days while stirring. It is filtered hot, the filtrate evaporated and the residue taken up in methylene chloride. The solution is shaken with 5% methanesulfonic acid, the aqueous phase made basic with ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the 3-methyl- 2,4-dioxo-8-(5-methoxy 2,3 dihydro 2 benzofurylmethyl)-1,3,8-triazaspiro(4,5)decane, showing in the I.R. spectrum bands at 3150, 1780, 1724 and 1600 cmf The starting material is prepared as follows: The solution of 20 g. of 8-benzyl-3-methyl-2,4-dioxo-1,3,8-triazaspiro(4,5)decane [Il. Pharmaco, 25, 681 (1970)] in 200 ml. of 90% aqueous acetic acid is hydrogenated over 5 g. of 10% palladium on charcoal at 55, until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate concentrated, the concentrate diluted with water and made basic with ammonia. The mixture is extracted with chloroform, the extract dried and evaporated, to yield the 3-methyl-2,4-dioxo-1,3,8-triazaspiro (4,5) decane.

Example 16 The mixture of 10 g. of 5-methoxybenzofuran-2-car boxaldehyde and 13 g. of 1-phenyl-4-oxo-1,3,8-triazaspiro (4,5 )decane, 0.5 ml. of acetic acid and 200 ml. of ethanol is refluxed for five hours under nitrogen. After cooling, 3 g. of 10% palladium on charcoal are added and the mixture hydrogenated at 3.3 atm. and 55' until the theoretical amount of hydrogen has been absorbed. It is heated to reflux, the mixture filtered hot, the filtrate slowly cooled and the precipitate formed filtered off, to yield the 1- phenyl-4-oxo-8-(5 methoxy 2,3-dihydro-Z-benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane melting at 191; it is identical with that obtained according to Example 1.

The starting material is prepared as follows: The mixture of 10 g. of 2-hydroxymethyl-S-methoxybenzofuran, 10 g. of active manganese dioxide and 100 ml. of methylene chloride is stirred at room temperature for 24 hours. It is filtered, the residue washed with hot methylene chloride and the combined filtrate evaporated, to yield the 5-methoxybenzofura.n-2-carboxaldehyde.

Example 17 Preparation of 10,000 tablets each containing 1.0 mg. of the active ingredient:

Formula: G.

l-phenyl 4 oxo 8 (5-methoxy-2,3-dihydro- 2 benzofurylmethyl)-l,3,8-triazaspiro(4,5) decane 10.00 Lactose 828.00 Corn starch 50.00 Polyethylene glycol 6,000 50.00 Talcum powder 50.00 Magnesium stearate 12.00 Purified water, q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 25 ml. of water and the suspension added to the boiling solution of the polyethylene glycol in 100 ml. of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm. openings and compressed into tablets using flat punches with 4.8 mm. diameter, uppers bisected.

Example 18 Preparation of 10,000 tablets each containing 25.0 mg. of the active ingredient:

Purified water, q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. The the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 45 ml. of water and the suspension added to the boiling solution of the polyethylene glycol in 180 ml. of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of Water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm. openings and compressed into tablets using concave punches with 7.1 mm. diameter, uppers bisected.

According to the procedure described in this and the preceding example, tablets are prepared, each containing 1 to 25 mg. of any compound of the invention, e.g. of those illustrated by the remaining examples herein.

Example 19 The solution of 5 g. of 2-bromomethyl-S-acetyl-2,3-dihydrobenzofuran in 40 ml. of 4-methyl-2-pentanone is added dropwise to the mixture of 4.5 g. of l-phenyl-4- oxo-1,3,8-triazaspiro(4,5)decane, 7.4 g. of sodium carbonate, 1 crystal of potassium iodide and 200 ml. of 4-methyl-2-pentanone while stirring. The mixture is refluxed 3 days, cooled and filtered. The precipitate is washed with 4-methyl-2-pentanone and water, the filtrate extracted with 5% hydrochloric acid and the aqueous solution made basic with ammonia. It is extracted with chloroform, the extract Washed with water, dried, evaporated and the residue recrystallized from acetone, to yield the l-phenyl 4 oxo 8 (5-acetyl-2,3-dihydro-2-benzofurylmethyl)-1,3,8-triazaspiro(4,5)decane, melting at 166- 168; it is identical with that obtained according to Example 14.

The starting material is prepared as follows: The mixture of 50 g. of 4-hydroxyacetophenone, 44.5 g. allylbromide, 51.5 g. of potassium carbonate and ml. of acetone is refluxed for 8 hours while stirring. After standing overnight at room temperature, it is diluted with 500 ml. of water and extracted with diethyl ether. The extract is washed with water, dried, evaporated, the residue distilled and the fraction boiling at 110-115 /0.7 mm. Hg collected, to yield the 4-al1yloxyacetophenone. 57 g. thereof are heated under nitrogen to 230 for minutes, cooled and diluted with 80 ml. of acetic anhydride. The

. 17 mixture is refluxed for 3 hours, evaporated, the residue distilled and the fraction boiling at 122128/0.2 mm. Hg collected, to yield the 4-acetyl-3-allylacetophenone.

To the solution of 52.5 g. thereof in 180 ml. of carbon disulfide, 38 g. of bromine are added dropwise during 3 hours while stirring at -5 to and the mixture evaporated under reduced pressure, to yield the 1,2-dibromo-3-(2-acetoxy acetylphenyl)-propane.

To the mixture of 100 g. thereof and 250 ml. of diethyl ether, the solution of 30 g. of sodium methoxide in 500 ml. of diethyl ether is slowly added while stirring and the mixture refluxed for 2 hours. It is cooled, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in water, the mixture extracted with methylene chloride, the extract washed with water, dried, evaporated, the residue distilled and the fraction boiling at 155-1577 0.07 mm. Hg collected, to yield the 2-bromomethyl-5- acetyl-2,3-dihydrobenzofuran.

Example 20 To the solution of 1.8 g. of 1-phenyl-4-oxo-8-(S-acetyl- 2,3-dihydro-Z-benzofurylmethyl) 1,3,8 triazaspiro(4,5) decane in 500 ml. of ethanol, 0.45 g. of sodium borohydride are added portionwise while stirring at 50. The mixture is slowly evaporated under reduced pressure, the residue triturated with water, filtered, washed with water and recrystallized from ethanol, to yield the 1-phenyl-4- oxo-8-[5-(l-hydroxyethyl) 2,3 dihydro-2-benzofurylmethyl]-1,3,8-triazaspiro(4,5)decane of the formula melting at 196-200.

Example 21 The mixture of 1.97 g. of l-2-(d-10-camphorsulfonyloxymethyl) 5 methoxy 2,3 dihydrobenzofuran, 20 ml. of dimethylformamide, 1.15 g. of 1-phenyl-4-oxo-1,3,8- triazaspiro(4,5)decane, 1.37 g. of potassium carbonate and 3 crystals of potassium iodide is refluxed for 15 minutes while stirring. It is evaporated under reduced pressure, the residue is taken up in 100 ml. of chloroform, the mixture washed twice with 50 ml. of water, dried and evaporated. The residue is recrystallized from 25 ml. of hot ethanol, and the precipitate formed after cooling is washed with ml. of cold ethanol, to yield the l-l-phenyl-4-oxo-8-(5-methoxy 2,3 dihydro 2 benzofurylmethyl) 1,3,8 triazaspiro(4,5)decane, melting at 188- 190; it is identical with that obtained according to Example 5 or 13.

The starting material is prepared as follows: To the solution of 206.5 g. of d,1-2-bromomethyl 5 methoxy- 2,3-dihydrobenzofuran and 105 g. of benzoic acid in 300 ml. of dimethylformamide, the suspension of 138.2 g. of potassium carbonate in 500 ml. of dimethylformamide is added during 14 minutes while stirring. After 12 minutes, the mixture is cooled, filtered and the residue washed twice with 100 ml. of dimethylformamide. The filtrate is concentrated, 500 g. of ice are added; whereupon crystallization occurs. The precipitate formed is filtered off, Washed with water, taken up in 2 1t. of diethyl ether, the solution washed with 100 ml. each of water, 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue is recrystallized from 800 ml. of isopropanol and washed with 400 ml. ice cold isopropanol, to yield the d,l-2-benzoyloxymethyl 5 methoxy 2, 3 dihydrobenzofuran, melting at 67-68".

150 g. thereof are added to the solution of 43.8 g. of potassium hydroxide in 500 m1. of anhydrous ethanol and the mixture is refluxed for 75 minutes, during which time 10 m1. portions of water are added to keep it homogeneous. It is evaporated under reduced pressure, the residue taken up in 200 m1. of water, the mixture concentrated 18 under reduced pressure and the concentrate extracted 5 times with 300 ml. of diethyl ether. The extract is dried, evaporated, the residue distilled and the fraction boiling at 108-110/0.1 mm. Hg collected, to yield the d,l-2-hydroxymethyl 5 methoxy 2, 3 dihydrobenzofuran, melting at 42-43".

To the solution of 39.08 g. thereof in 350 ml. of pyridine, 56.13 g. of d-l0-camphorsulfonylchloride are added during 15 minutes while stirring and keeping the temperature between 18 and 20. The mixture is allowed to stand overnight at room temperature and is evaporated under reduced pressure. The residue is distributed between 600 ml. of methylene chloride and 1.37 It. of 4% ice cold hydrochloric acid. The organic phase is separated, washed with water, dried filtered and evaporated. The residue is recrystallized from 875 ml. of methanol and washed twice with ml. of methanol. It is again recrystallized from 600 ml. boiling methanol, the precipitate formed at room temperature filtered oif and washed twice with 125 ml. of methanol, to yield the l-2-(d-IO-camphorsulfonyloxymethyl) 5 methoxy 2, 3 dihydrobenzofuran, melting at Ill-112, [a] =20.5 (chloroform).

The combined mother liquors are cooled to -15, the precipitate formed filtered off and washed twice with 125 ml. of 15 methanol, to yield d-Z-(d-IO-camphorsulfonyloxymethyl) 5 methoxy 2, 3 dihydrobenzofuran, melting at 60-62, [u] =+65.8 chloroform). It can be converted into d,l -2 hydroxymethyl 5 methoxy 2,3-dihydrobenzofuran as follows.

The mixture of 15.7 g. of the undesired, low melting d-camphorsulfonate, 5.49 g. of benzoic acid, 13.7 g. of potassium carbonate and 100 ml. of dimethylformamide is refluxed for 30 minutes while stirring. It is evaporated under reduced pressure, the residue taken up in 250 ml. of water and the mixture extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from diisopropyl ether, to yield the d 2 benzoyloxymethyl 5 methoxy 2, 3 dihydrobenzofuran, melting at 62-68.

9.39 g. thereof are added to the solution of 3.36 g. of potassium hydroxide in 50 ml. of ethanol and 10 ml. of Water and the mixture refluxed for 30 hours. It is evaporated under reduced pressure, the residue taken up in water and the mixture extracted with diethyl ether. The extract is dried, filtered, evaporated, the residue distilled and the fraction boiling at 114116/0.18 mm. Hg collected, to yield the d 2 hydroxymethyl 5 methoxy 2,3-dihydrobenzofuran, [a] =+41.7 (chloroform).

The mixture of 2.5 g. thereof, 50 ml. of dry toluene and 25 mg. of sodium is refluxed until the sodium is consumed. Thereupon the solution of 90 mg. of 9-fluorenone in 1.5 ml. of toluene is added and the mixture refluxed for 28 hours. It is cooled, washed with water, dried, evaporated, the residue distilled and the fraction boiling at 114-116/ 0.18 mm. Hg collected, to yield the almost racemic 2- hydroxymethyl 5 methoxy 2,3 dihydrobenzofuran, ]n=+13.4 (chhloroform).

Said intermediate can also be prepared as follows: Through the stirred mixture of 12.4 g. 4-methoxyphenol, 13.03 g. of a-chloroacrylonitrile and 13.63 g. of zinc chloride, hydrogen chloride is bubbled while keeping the temperature at about 40 for 2 hours. The mixture is allowed to cool to room temperature, 4.5 g. of a-chloroacrylonitrile are added while stirring and the mixture allowed to stand overnight at room temperature. Thereupon 80 ml. of water and 250 ml. of methylene chloride are added while stirring, the organic solution separated, dried and evaporated. The residue is taken up in the solution of 20 g. of potassium hydroxide, 50 ml. of water and 50 ml. of ethanol and the mixture refluxed overnight. After cooling, it is acidified with concentrated hydrochloric acid and evaporated under reduced pressure. The residue is taken up in ml. of water, the mixture extracted with chloroform, the extract dried, evaporated and the residue recrystallized from chloroform, to yield the d,l-5-methoxy- 2,3 dihydro 2 benzofurancarboxylic acid, melting at 98-l00. It can be reduced to the corresponding alcohol as shown in Example 13.

Instead of treating the resulting condensation product, i.e. the 3 chloro 6 methoxy 3, 4 dihydrocoumarin, with potassium hydroxide, it is taken up in the minimum amount of dioxane, the solution slowly added to 75 ml. of concentrated aqueous ammonia while stirring at 10, the mixture stirred at room temperature for about 2 hours and filtered, to yield the d,l 5 methoxy 2, 3 dihydro- 2 benzofurancarboxamide. It is analogously reduced with lithium aluminum hydride, to yield the d,l-2-aminomethyl-S-methoxy-Z,3-dihydrobenzofuran.

Example 22 Preparation of 10,000 capsules each containing mg. of the active ingredient:

Formula: G.

l-phenyl 4 oxo-8-[5-(1-hydroxyethyl)-2,3- dihydro-2benzofurylmethyl] 1,3,8 triazaspiro(4,5)decane 100.0 Lactose 1,800.0 Talcum powder 100.0

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 3 capsules are filled with 200 mg., using a capsule filling machine.

Example 23 Preparation of injectable solutions containing 1% of the active ingredient:

0.1 Molar aqueous citric acid, 4 1t. Water for injection, q.s.

Procedure The trichloropropanol is dissolved in 12 1t. of water at 90, then the carboxymethylcellulose is added while stirring, followed by the methylcellulose. The solution obtained is allowed to stand at 10 for 12 hours, whereupon the polysorbate and sodium chloride are added. The triazaspirodecane is dissolved in the citric acid at 60, the solution cooled to room temperature, combined with the previous solution and the whole made up to 17 It. with Water. The resulting mixture is filtered through sinter glass, sterilized at 100 for 3 hours and minutes, cooled, filled into sterile vials of 2 or 5 ml. content, which are sealed.

Analogous solutions can be obtained by replacing the triazaspirodecane by the corresponding methanesulfonate of Example 6 and the citric acid by water. Also the other compounds, illustrated by the previous examples, can be used for the above composition, using advantageously citric acid as the salifying agent.

Example 24 The mixture of 5 g. of 1-(5-methoxy-2,3-dihydro-2- benzofurylmethyl) 4 phenylamino-hexahydroisonicotinamide (Example 10) and ml. of formamide is heated to 170 for 12 hours while stirring. After cooling it is diluted with 100 ml. of water, the mixture extracted with 200 ml. of chloroform, the extract dried, evaporated under reduced pressure and the residue recrystallized from isopropanol, to yield the 1-pheny1-4-0x0-8-(S-methoxy- 20 2,3-dihydro 2 benzofurylmethyl)-1,3,8-triazaspiro(4,5) decane, melting 188-191; it is identical with the product obtained according to Example 1.

Example 25 The mixture of 1 g. of 1-(5-methoxy-2,3-dihydro-2- benzofurylmethyl)-4-phenylarnino hexahydroisonicotinamide, 0.1 ml. of acetic acid and 100 ml. of dimethoxymethane is refluxed for 36 hours in a Soxhlet apparatus, passing the condensate over a molecular sieve removing methanol. It is evaporated under reduced pressure, the residue triturated with water, the mixture made basic with aqueous ammonia, filtered and the residue recrystallized from isopropanol, to yield the 1-phenyl-4-oxo-8-(5- methoxy-2,3-dihydro 2 benzofurylmethyl)-1,3,8-triazaspiro(4,5)decane, melting at 188191.

Example 2 6 The mixture of 5 g. of 1-(5-methoxy-2,3-dihydro-2- benzofurylmethyl)-4-phenylamino hexahydroisonicotinic acid nitrile, 50 ml. of dimethylformamide, 0.5 g. of paraformaldehyde and 2 g. of methanesulfonic acid is heated on the steam bath for 24 hours while stirring. After cooling 1.2 g. of sodium methoxide are added while stirring and heating is continued for 12 hours. The mixture is evaporated under reduced pressure, the residue taken up in water, the mixture filtered and the residue recrystallized from isopropanol, to yield the l-phenyl-4-oxo-8-(5- methoxy-2,3-dihydro 2 benzofurylrnethyl)-1,3,8-triazaspiro(4,5)decane, melting at 188-19l.

The starting material is prepared as follows:

To the mixture of 61.2 g. of sodium bis-(2-methoxyethoxy)-aluminum hydride and 500 ml. of toluene, 19.3 g. of d,1-5-methoxy-2,3-dihydro-2-benzofurancarboxamide (mp. 150-153", Example 21) are added por-tionwise and the mixture stirred overnight at room temperature. Thereupon 85 ml. of 20% aqueous sodium hydroxide are added dropwise, stirring is continued for 10 minutes, the organic solution decanted off, dried, evaporated, the residue distilled and the fraction boiling at 103l06/0.15 mm. Hg collected, to yield the Z-aminomethyl-S-methoxy- 2,3-dihydrobenzofuran.

The mixture of 1.79 g. thereof, 10 ml. of ethyl acrylate and 2 drops of 70% aqueous perchloric acid is refluxed for 21 hours. It is concentrated under reduced pressure, the concentrate combined with ml. of toluene, the mixture washed with saturated aqueous sodium bicarbon ate, dried, filtered and evaporated, to yield the 2-[bis-(2- carbethoxyethyl) aminomethyl]-5-methoxy-2,3dihydrobenzofuran.

4.12 g. thereof are added during 30 minutes to the mixture of 0.84 g. of 57% sodium hydride and mineral oil, 10 ml. of toluene and 2 drops of ethanol while stirring at 6070. After one hour 30 ml. of 6N hydrochloric acid are added and the mixture heated to the boil until the toluene is distilled off. Refiuxing is continued until one drop of the reaction mixture no longer gives a red color with 1% aqueous ferric chloride (about two hours). The mixture is cooled, washed with toluene and made basic with solid sodium hydroxide. It is extracted with toluene, the extract dried and evaporated under reduced pressure. The residue is taken up in diethyl ether, the solution filtered through diatomaceous earth, the column eluted with methylene chloride, the eluate evaporated and the residue recrystallized from diisopropyl ether, to yield the 2-(4- oxopiperidinornethyl) 5-methoxy-2,3-dihydrobenzofuran.

To the mixture of 2.61 g. thereof, 10 ml. of acetic acid and 1 g. of aniline, the solution of 0.5 g. of sodium cyanide in 2 m1. of water is added and the mixture stirred overnight at room temperature. It is poured into aqueous ammonia and ice and the mixture extracted with chloroform. The extract is dried, filtered and evaporated, the residue taken up in diethyl ether, the solution filtered through diatomaceous earth and the column eluted with me hylene chloride. Th eluate is evapo a ed and-the residue recrystallized from diisopropyl ether, to yield the 1-(5-methoxy-2,3-dihydro 2 benzofurylmethyl)-4-phenylamino-hexahydroisoniootinic acid nitrile melting at 131-133.

What is claimed is:

1. A l-[l-(2,3-dihydro-Z-benzofuryl)-alkyl]-4-aminohexahydroisonicotinic acid amide or nitrile corresponding to the formula wherein Ph is 1,2-phenylene, (lower alkyl)-1,2-phenylene, monoor di-(lower alkoxy)-1,2-phenylene, (lower alkylenedioxy)-1,2-phenylene, (fluoro or chloro)-1,2-phenylene, (lower a-hydroxyalkyl)-1,2-phenylene or (lower alkanoyl)-1,2-phenylene, each of R R and R is hydrogen or lower alkyl, each of alk and alk is lower alkylene separating the nitrogen atom from the Spiro-carbon atom by two ring-carbon atoms, R is hydrogen, lower alkyl, 3 to 7 ring-membered cycloalkyl or H-Ph, Z is COHNR or CN and R is hydrogen, lower alkyl or lower hydroxyalkyl, or an alkali metal or acid addition salt thereof.

2. A compound as claimed in claim 1 and corresponding to the formula in which R-, is hydrogen, lower alkyl, lower al-koxy, fluoro, chloro, lower a-hydroxyalkyl, or lower alkanoyl,

each of R and R is hydrogen or lower alkyl, R is lower alkyl, 3 to 7 ring-membered cycloalkyl or R -phenyl, Z is CONHR or CN and R is hydrogen, lower alkyl or hydroxy-lower alkyl, or an alkali metal or acid addition salt thereof.

3. A compound as claimed in claim 2, in which formula R is hydrogen, alkyl, alkoxy, fluoro, chloro, a-hydroxyalkyl, or alkanoyl, each of R and R is hydrogen or methyl, R is methyl, cyclohexyl or R -phenyl, Z is CO NHR or CN and R is hydrogen, methyl or hydroxymethyl, and alkyl, alkoxy or alkanoyl contains up to 4 carbon atoms, or an alkali metal or acid addition salt thereof.

4. -A compound as claimed in claim 2, in which formula R is hydrogen, methyl, methoxy, fluoro, chloro, l-hydroxyethyl or acetyl, Z is CONHR or CN, each of R R and R is hydrogen or methyl and R is R -phenyl, or an alkali metal or acid addition salt thereof.

5. A compound as claimed in claim 2 and being the 1-(5-methoxy 2,3 dihydro 2 benzofury1methyl)-4- phenylamino -hexahydroisouicotinamide, or an alkali metal or acid addition salt thereof.

6. A compound as claimed in claim 2 and being the I-(S-methoxy 2,3 dihydro 2 benzofurylmethyl)-4- phenylamino-hexahydroisonicotinic acid nitrile, or an alkali metal or acid addition salt thereof.

References Cited UNITED STATES PATENTS G. THOMAS TODD, Primary Examiner 

1. A 1-(1-(2,3-DIHYDRO-2-BENZOFURYL)-ALKYL)-4-AMINOHEXAHYDROISONICOTINIC ACID AMIDE OR NITRILE CORRESPONDING TO THE FORMULA 